There are currently several antipsychotics available for regular clinical use. Every one of them blocks dopamine D2 receptors (Seeman and Tallerico 1998). See Index of Articles cited herein. This includes the older “typical” as well as the newer “atypical” antipsychotics. “Atypical” antipsychotic is a term that is used to define antipsychotics which have a lower or minimal incidence of side effects. With the exception of a few dopamine-depleting agents, there is no receptor-drug profile other than D2 receptor blockage that is able to achieve antipsychotic activity. However, a central problem in the use of antipsychotics is that of related side effects. The two major side effects of concern have been extrapyramidal side effects (“EPS”) as well as prolactin elevation. Side effects limit the number of patients who agree to take these medications, as they tend to decrease compliance and high levels of EPS may actually decrease the efficacy of the medications.
Without being bound by theory, it is believed that EPS and prolactin elevation also result from dopamine D2 blockade. In particular, the blockade of D2 receptors in the tubero-infundibular system is thought to be responsible for prolactin elevation (Moore 1987), while the blockade of the dopamine D2 receptors in the striatum is thought to be responsible for EPS (Farde et al. 1997). A corollary of prolonged blockade of the dopamine D2 system is thought to be tardive dyskinesia which occurs after several years of use of antipsychotics that cause EPS (Casey 1996). Thus, avoiding these side effects is a central way of improving antipsychotics.
The current gold-standard for an a typical antipsychotic is clozapine. However, in some patients clozapine has the serious shortcoming of blood dyscrasias, or agranulocytosis, which means that all patients on this medication must have their blood tested regularly. This side-effect is the Achille's heel of clozapine. It has limited the use of this most effective antipsychotic (in terms of efficacy and “atypicality”) to being the drug of last resort because of this ongoing need for regular blood testing of each patient on the medication.
There is therefore a need for new effective antipsychotic drugs exhibiting minimal side effects (e.g., diminished or absent EPS, prolactin elevation and/or agranulocytosis side effects).